Following axonal injury, neurons of the mammalian central nervous system (CNS) have a poor capacity for axonal regeneration. By contrast, neurons of the mammalian peripheral nervous system (PNS) have a substantially greater capacity for axonal regeneration. See Schwartz et al., 1989, FASEB J. 3:2371-2378.
The difference between axonal regeneration in the CNS and PNS has been attributed to the cellular environment of the neurons rather than to the neurons themselves. Following neuronal injury, the Schwann cells that surround PNS neurons are modulated so as to become permissive or supportive for axonal regeneration. By contrast, the astrocytes, oligodendrocytes and microglia that surround CNS neurons do not show such modulation and remain unsupportive or inhibitory for axonal regeneration. See Schwartz et al., 1987, CRC Crit. Rev. Biochem. 22:89-110.
This lack of modulation has been correlated with differences in the post-injury inflammatory response. See Perry and Brown, 1992, Bioessays 14:401-406; Lotan and Schwartz, 1994, FASEB J. 8:1026-1033. In particular, the accumulation of mononuclear phagocytes in response to CNS injury is delayed and limited in comparison with the response to injury in the PNS. This limited CNS mononuclear phagocyte response may in turn lead to (1) inefficient removal of the myelin debris that reportedly inhibits axonal regeneration, and (2) suboptimal release of macrophage-derived cytokines that would promote modulation of astrocytes and oligodendrocytes so as to support axonal regeneration.
The above observations have prompted speculation that appropriate modulation of the macrophage response might promote axonal regeneration after CNS injury. In an in vitro system, David et al. showed that when cryostat sections of normal rat optic nerve are co-cultured with mononuclear phagocytes derived from lesions of the rat CNS, the optic nerve sections show enhanced adhesiveness for embryonic chick dorsal root ganglion cells. David et al., 1990, Neuron 5:463-469. Conditioned medium from activated peritoneal macrophages was also effective in promoting adhesiveness of optic nerve sections in this in vitro assay.
However, results derived from in vivo models of CNS injury have revealed that some interventions that enhance the macrophage response to CNS injury do not result in enhanced regeneration. For instance, local injection of either tumor necrosis factor alpha (TNF-.alpha.) or colony stimulating factor-1 (CSF-1) enhanced the macrophage response to experimental optic nerve injury. However, only TNF-.alpha., but not CSF-1, increased the permissiveness of the injured optic nerves for neuronal adhesion as assayed in vitro. Lotan et al., 1984, Exp. Neurol. 126:284-290. It has been suggested as one possible explanation that "only appropriately stimulated macrophages can influence neuronal regeneration." Schwartz et al., 1994, Progress Brain Res. 103:331-341, at 338.
In fact, contrary to the teaching of the present invention, other investigators have reported that mononuclear phagocytes might exacerbate damage or limit recovery following CNS injury. Brain macrophages, when stimulated by cytokines, exhibit neurotoxic activity. Chamak et al., 1994, J. Neurosci. Res. 38:221-233. Pharmacological inhibition of mononuclear phagocyte function has been reported to promote recovery in a rabbit model of spinal cord injury. Giulian and Robertson, 1990, Annals Neurol. 27:33-42. It has been suggested that macrophage-derived cytokines may promote formation of glial scars and thereby inhibit axonal regeneration. Khan and Wigley, 1994, NeuroReport 5:1381-1385; Vick et al., 1992, J. Neurotrauma 9:S93-S103.
Citation or identification of any reference in Section 2 (or any other section) of this application shall not be construed as an admission that such reference is available as prior art to the present invention.